Care in the hands of a healer

Paul Carpenter finds fulfillment through connections made with young patients and their families, and research toward eliminating GVHD

April 7, 2005

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By COLLEEN STEELQUIST

In addition to working on antibody therapy for graft-vs.-host disease, pediatric physician and researcher Dr. Paul Carpenter is designing a study to look at the potential drug interactions of cholesterol-lowering medications in transplant patients.

Photo by Todd McNaught

Inside the austere white binders that line the shelves of Dr. Paul Carpenter's office, you'll find plenty of study records and technical data, but you'll also find something else — his heart.

Interspersed with the research annals, mementos from grateful patients spill forth from notebooks: Christmas cards, school photos, notes of heartfelt thanks, graduation announcements and more. All are poignant reminders of Carpenter's calling and motivation as a healer.

But the role of healer takes Carpenter beyond hands-on contact with the infirm. As the only Clinical Research Division clinician with a foot in both pediatric and adult camps, Carpenter's duties shift between pediatric bone-marrow transplant patients, long-term follow-up care for both adult and pediatric patients and research, mainly focused on graft-vs.-host disease (GVHD). He's helped make key advances in treating this sometimes life-threatening transplant complication.

Carpenter feels he has found the perfect balance in his professional aims at Fred Hutchinson. Every other month, he dons his physician hat and sees patients full-time: children at the Seattle Cancer Care Alliance clinic or Long-Term Follow-Up (LTFU) patients. He also fields phone calls from physicians around the country who have care questions about their patients previously treated at the center.

On opposite months, he hangs up his stethoscope and reconnects with research.

As a child, Carpenter's fascination with the biology of his small pets and critters had him thinking about becoming a veterinarian. He realized, though, that biology had to be linked with a human element to bring him satisfaction. "I need that interaction with the patient to make it relevant," he said.

Carpenter went to medical school at the University of Sydney in his native Australia. During his pediatric medical training, he was drawn to families facing cancer. "In general pediatrics, my sense was that a lot of conditions get better without a great need for medical intervention, but cancer does not. You've got these profoundly ill children, and pediatric oncologists have made huge gains over the years. It's inspiring to be part of potentially making progress in that regard. It really made me think, 'This is what I want to do.'"

Today, much of Carpenter's job and personal fulfillment comes from connecting emotionally with young patients and their families.

"One of the things that many people say about working with sick kids is, 'How can you do that? It must be so sad,'" Carpenter said. "But I love interacting with the families in good and bad situations. You can turn a bad situation into a very good situation if the outcome is positive. But even if the child ultimately dies, you can make that situation less horrible than it otherwise would be. So no matter what the situation, I always feel like I can help in some way."

Carpenter certainly helped Hannah, who was treated at the center 9 years ago. A framed photo — updated annually by her family — of the bespectacled little girl with an impish grin sits next to his desk in the Thomas building. The youngster, once a 2-year-old patient, had neuroblastoma, one of the most common solid tumors in children. Because of her cancer's advanced stage, she was given a less than 20 percent chance of survival.

"She had the disease in her abdomen and many of her bones, including a tumor in an eye socket that was severely compromising her vision. She relapsed just before her transplant. I treated her with a more aggressive therapy that I had used in Australia, and we got her back into remission," he said. "You really remember the ones who had such poor prognosis, and the situation could be turned around. It was just amazing."

Carpenter came to the United States in 1995 as part of the University of Washington's hematology fellowship program and began his work at Fred Hutchinson. Initially, Carpenter only planned to get more oncology training in the States and then return home. "To get a pediatric-transplant job in Australia, you have to go overseas to get experience because the competition is fairly tight for basically 30 slots in the whole country," he said.

However, Carpenter's success at Fred Hutchinson took his professional plans in a different direction. As the recipient of a two-year Young Investigator Award in 1998 from the American Society of Clinical Oncology and a three-year Leukemia and Lymphoma Society research fellowship in 1999, Carpenter stayed at the center and forged a career.

Early work at Fred Hutchinson

He initially worked in Dr. Claudio Anasetti's Clinical Research Division lab, doing bench research in antibody therapy for GVHD treatment. GVHD is a common post-transplant side effect in which the donor T cells recognize the transplant recipient's tissues as foreign and attack them. GVHD can be acute — occurring just after a transplant and potentially life-threatening — or chronic. "It's the number one reason why transplants are not a home run, even though in our transplants for malignancies, we know that a little bit of GVHD reduces the risk of relapse," Carpenter said.

It has long been observed that cancer patients who experience GVHD after their transplants tend to have better cancer-free survival than patients who do not. The reason for the increased survival rate is that the donor T cells recognize any residual cancer cells and eliminate them, a welcome reaction called graft-vs.-leukemia effect. However, for transplant patients with non-malignant diseases, such as aplastic anemia, GVHD provides no benefit.

Chronic GVHD is generally less dangerous for the patient than acute GVHD, but it can cause a host of symptoms like dry eyes and mouth and lung and joint problems. Chronic GVHD subsides in most patients after several years of treatment with prednisone (a steroid), but the drugs often have the undesired effect of suppressing the immune system.

GVHD antibody therapy

Even well into the 1990s, several studies have shown that patients with severe prednisone-resistant acute GVHD had a one-year survival rate of no better than 12 percent. In the lab, Carpenter developed potent antibody therapy to reduce the occurrence of GVHD. A phase I trial showed a 60 percent one-year survival rate; however, a multi-center study of the same antibody found a 30 percent success rate and an increased risk of infection. "In our hands, it's still better than 12 percent, but it's certainly got a long way to improve," Carpenter said.

"We've still got a great distance to go with specific treatments for GVHD that don't shift the balance toward more infections," he said. "We're testing new drugs, and we're learning more, but we still haven't come up with the magic bullet."

"One thing that's led to an increase in chronic GVHD is the use of blood stem-cell transplants and more mismatched donors. It's a double-edge sword: stem-cell transplants have made overall survival go up, but they do set the patients up for more health problems caused by being on medication longer for chronic GVHD."

Carpenter joined the LTFU staff in 2001, enabling him to pursue his dual loves of patient care and research. "I could probably get by only seeing patients, but I really wanted to bring those experiences and outcomes — especially the negative ones — back to the research side," he said. "I ask, 'How can I improve on this?' I'm always dreaming up new things."

He is currently designing a study to look at the potential drug interactions of cholesterol-lowering medications in transplant patients. Many patients experience elevated cholesterol levels after their transplants, but doctors currently do not treat them, fearing side effects from medications. "Why have we been ignoring this for so long?. Cholesterol-lowering drugs might have other benefits in these patients besides reducing the risk of heart disease," he said. "They might improve kidney function, lower blood pressure, or protect against some of the side effects of prednisone on the bones. All of these things make a compelling argument to revisit the question."

Prednisone therapy reduction

Carpenter is also planning to test a new antibody therapy in GVHD treatment. If successful, it would allow doctors to reduce the amount of prednisone a patient receives. Since prednisone therapy brings significant side effects, lowering its use would bring tangible benefits. "Even though prednisone is our number one drug for GVHD, it's also the root of all evil in terms of infectious risks and complications," he said.

The knowledge Carpenter brings from the research and clinical worlds is not only appreciated by his patients, but also by his colleagues. "Paul is a meticulous physician with a warm bedside manner," said Dr. Mary Flowers, medical director of the LTFU program. "His experience in several GVHD clinical trials has been a great asset for our program. Paul is a very thoughtful person and a great collaborator — and he has a unique, Australian sense of humor!"

Carpenter reciprocates the enthusiasm for his colleagues. "Both the LTFU and pediatric staff are a great bunch of people to work with," he said. "It's very important to me to work with people who are inspiring and have a great patient care and research ethic combined into one." He says he's proud of being a part of conducting sound clinical research at an institution where it's possible to get things done.

Carpenter's goal

The National Institutes of Health — acknowledging the combined expertise that Drs. Carpenter, Flowers and Paul Martin, who directs LTFU research, bring to the field — asked the trio to serve on an ongoing consensus committee for setting diagnostic parameters for chronic GVHD. "I encounter problems all of the time when I'm doing clinical work: there are a lot of patients outside of the Fred Hutchinson umbrella who are not having their chronic GVHD diagnosed. It's not being treated adequately," Carpenter said. "The wider community needs to be able to make the diagnosis of chronic GVHD and treat it better."

For now, eliminating GVHD as a threat remains a worthy but elusive goal for Carpenter. "I really hope to make a serious dent in treating GVHD. If we can meaningfully reduce steroid doses by introducing some novel and effective drug at the beginning of GVHD treatment, it could change standard practice. Within the transplant community, that's the Holy Grail — to control GVHD yet not increase the risk of relapse."